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Related Concept Videos

Cooperative Allosteric Transitions01:58

Cooperative Allosteric Transitions

Cooperative allosteric transitions can occur in multimeric proteins, where each subunit of the protein has its own ligand-binding site. When a ligand binds to any of these subunits, it triggers a conformational change that affects the binding sites in the other subunits; this can change the affinity of the other sites for their respective ligands. The ability of the protein to change the shape of its binding site is attributed to the presence of a mix of flexible and stable segments in the...
Cooperative Allosteric Transitions01:58

Cooperative Allosteric Transitions

Cooperative allosteric transitions can occur in multimeric proteins, where each subunit of the protein has its own ligand-binding site. When a ligand binds to any of these subunits, it triggers a conformational change that affects the binding sites in the other subunits; this can change the affinity of the other sites for their respective ligands. The ability of the protein to change the shape of its binding site is attributed to the presence of a mix of flexible and stable segments in the...
Cooperative Allosteric Transitions01:58

Cooperative Allosteric Transitions

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Insertion of Multi-pass Transmembrane Proteins in the RER01:29

Insertion of Multi-pass Transmembrane Proteins in the RER

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Transmembrane Domain Dominance Drives Emergent Signaling and Allosteric Inversion in mGlu1/5 Heterodimers.

Justin B Steinfeld1,2,3, Xia Lei4,5, Madeline Laramee1,2

  • 1Department of Psychiatry, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, USA.

Biorxiv : the Preprint Server for Biology
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Summary

Class C GPCRs signal as dimers. This study reveals mGlu₁/₅ heterodimer signaling favors the mGlu₁ protomer, impacting drug development for metabotropic glutamate receptors.

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Area of Science:

  • Neuroscience
  • Pharmacology
  • Molecular Biology

Background:

  • Class C GPCRs form obligate dimers, but protomer contribution to signaling is unclear.
  • Understanding heterodimer signaling is crucial for developing selective drugs.
  • Metabotropic glutamate receptors (mGluRs) are key targets.

Purpose of the Study:

  • To investigate the distinct roles of mGlu₁ and mGlu₅ protomers in mGlu₁/₅ heterodimer signaling.
  • To characterize the influence of protomer dominance on allosteric modulator activity.
  • To explore new pharmacological strategies for selective targeting of mGluR dimers.

Main Methods:

  • Utilized CODA-RET, a BRET-based assay, to measure direct Gαq recruitment.
  • Employed full-length receptor pairs and domain-swapped chimeras.
  • Tested the effects of cis-acting and trans-acting allosteric modulators.

Main Results:

  • Signaling in mGlu₁/₅ heterodimers predominantly flows through the mGlu₁ protomer, localized to the transmembrane domain.
  • Cis-acting mGlu₁ positive and negative allosteric modulators showed inverted activity when signaling was restricted to mGlu₅.
  • mGlu₅-selective negative allosteric modulators were inactive at the heterodimer.

Conclusions:

  • Protomer dominance in Class C GPCR heterodimers creates emergent signaling properties.
  • Pharmacological interventions can be tuned by targeting specific protomers and their mode of action (cis vs. trans).
  • This work provides a framework for designing selective drugs targeting mGluR homomers and heterodimers.